Repeated exposure to social defeat stress in rats induces behavioral cross-sensitization to psychostimulant drugs and vulnerability to addiction. An animal model of psychosocial stress resulting in measurable behavioral changes analogous to human behavior may be relevant for investigating the link between stress and addiction. Although it is well known that the mesocorticolimbic dopamine system is essential for induction of behavioral sensitization, the mechanism by which social stress causes cross- sensitization is unknown. The main goal of this proposal is to elucidate the role of brain-derived neurotrophic factor (BDNF) in the anterior cingulate, prelimbic and infralimbic regions of prefrontal cortex (PFC) for social stress-induced cross-sensitization. Our preliminary data provide evidence of transient and prolonged alterations of BDNF expression in dopaminergic areas following repeated social defeat stress exposure. Specifically, our data show that repeated social defeat stress increased BDNF protein and mRNA expression in rat PFC immediately after stress episodes and in the ventral tegmental area (VTA) four weeks later. We hypothesize that stress-induced BDNF expression in PFC may trigger persistent neuronal plasticity in the VTA thereby inducing behavioral cross-sensitization to psychostimulants In Specific Aim 1, we will elucidate the role of BDNF in the PFC in social stress-induced cross- sensitization by sustained deletion or over-expression of BDNF locally via adeno-associated virus- mediated gene delivery. Specific Aim 2 will define the role of BDNF in PFC-VTA connections in persistent neuroadaptation in the VTA after social defeat stress. The identification and characterization of specific neuroadaptive changes resulting from repeated social stress exposure leading to increased drug vulnerability is a major requirement for the development of effective prevention strategies. The research proposed herein will determine the role of brain derived neurotrophic factor (BDNF) in response to social stress exposure in brain areas involved in long-term sensitization to psychostimulants. Recognition of such a specific role of BDNF will provide insight into neuroadaptive events following social defeat stress, and will also aid in identifying new pharmacotherapeutic targets for treating addiction.